TY - JOUR T1 - <strong>Regulation of intestinal UGT1A1 by the FXR agonist obeticholic acid (OCA) is controlled by CAR through intestinal maturation</strong> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000240 SP - DMD-AR-2020-000240 AU - Andre W Weber AU - Elvira Mennillo AU - Xiaojing Yang AU - Lori W.E. van der Schoor AU - Johan W Jonker AU - Shujuan Chen AU - Robert H. Tukey Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/11/05/dmd.120.000240.abstract N2 - UDP-glucuronosyltransferase 1A1 (UGT1A1) is the only transferase capable of conjugating serum bilirubin. However, temporal delay in the development of the UGT1A1 gene leads to an accumulation of serum bilirubin in newborn children. Neonatal humanized UGT1 mice (hUGT1), which accumulate severe levels of total serum bilirubin (TSB), were treated by oral gavage with obeticholic acid (OCA), a potent FXR agonist. OCA treatment led to dramatic reduction in TSB levels. Analysis of UGT1A1 expression confirmed that OCA induced intestinal and not hepatic UGT1A1. Interestingly, Cyp2b10, a target gene of the nuclear receptor CAR, was also induced by OCA in intestinal tissue. In neonatal hUGT1/Car-/- mice, OCA was unable to induce CYP2B10 and UGT1A1, confirming that CAR and not FXR is involved in the induction of intestinal UGT1A1. However, OCA did induce FXR target genes like Shp in both intestines and liver with induction of Fgf15 in intestinal tissue. Circulating FGF15 activates hepatic FXR and together with hepatic Shp blocks Cyp7a1 and Cyp7b1 gene expression, key enzymes in bile acid metabolism. Importantly, the administration of OCA in neonatal hUGT1 mice is accelerating intestinal epithelial cell maturation, which directly impacts on induction of the UGT1A1 gene and the reduction in TSB levels. Accelerated intestinal maturation is directly controlled by CAR, since induction of enterocyte marker genes Sis, Akp3 and Krt20 by OCA does not occur in hUGT1/Car-/- mice. Thus, new findings link an important role for CAR in intestinal UGT1A1 induction and its role in the intestinal maturation pathway Significance Statement Obeticholic acid (OCA) activates FXR target genes in both liver and intestinal tissues while inducing intestinal UGT1A1 which leads to the elimination of serum bilirubin in hUGT1 mice. However, the induction of intestinal UGT1A1 and the elimination of bilirubin by OCA is driven entirely by activation of intestinal CAR, and not FXR. The elimination of serum bilirubin is based on a CAR dependent mechanism that facilitates the acceleration of IEC differentiation, an event that underlies the induction of intestinal UGT1A1 ER -